Our goal is to generate a mouse model that closely resembles Alzheimer's Disease. In our first attempt we have developed two mouse models of AD that progress from A[unreadable] production and amyloid deposition to hyperphosphorylated native mouse tau at AD-associated epitopes, redistribution of tau to somatodendritic regions of neurons, aggregated tau, significant neuronal loss, robust behavioral changes and neurovascular unit involvement (see preliminary data). These new models express human APP mutations on a mouse nitric oxide synthase 2 (NOS2) knockout background. NOS2 and its gene product, iNOS play an important role in neuroinflammation by generating nitric oxide (NO), a critical signaling and redox factor in the brain. Neuroinflammation is an invariant feature of chronic neurodegenerative disease. Importantly, critical differences exist in the NOS2 gene that impact the production of NO during an immune response in humans compared to rodent. Genetic deletion of the NOS2 gene in mouse in the presence of mutated human APP has provided important insights into the pathology of AD. However, we hypothesize that a targeted replacement mouse where the human NOS2 gene including the promoter replaces the mouse NOS2 gene and that also expresses mutated human APP will be a defining model for AD. This R21/R33 project proposes to develop such a mouse in the R21 phase and then to phenotype the resulting pathology and test the amyloid cascade hypothesis in the R33 phase. PUBLIC HEALTH RELEVANCE: Our goal is to generate a mouse model that closely resembles Alzheimer's Disease. We hypothesize that a mouse with a more human-like immune response (in which the NOS2 mouse gene is replaced by a human NOS2 gene) and expresses human mutated amyloid precursor will promote progression of the disease beyond amyloid deposition alone. This will provide a realistic mouse model of AD to study and to use in the development of rational and effective therapeutics for AD.